Epidemiologic studies over the past decade suggest an inverse association of dietary folate (vitamin B9) intake with the risk of cancers of the liver and intestine. Folate plays a central role in one carbon metabolism and significantly impacts DNA synthesis by contributing to dNTP biosynthesis. Folate also impacts DNA methylation by contributing to biosynthesis of S-adenosylmethionine (SAM), the methyl donor molecule used by DNA methyltransferases. Prostate epithelial cells place an unusually high demand on these metabolic pathways because SAM is pulled from the system by decarboxylation due to the extraordinarily high level of polyamine catabolism in these cells. Deficiencies in these pathways are known to cause genetic damage as well as epigenetic damage in the form of global hypomethylation and CpG island specific hypermethylation. We hypothesize that the prostate is exquisitely sensitive to manipulation of folate in the diet due to its unusually high demand on the metabolic pathways folate is central to. Furthermore, we predict that altering dietary folate can influence the tumorigenic progression in prostate cancer (CaP) by influencing the genetic and epigenetic damage critical to the tumorigenic process. We will test this hypothesis by altering the dietary folate in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model that develops progressive stages of prostatic disease similar to CaP in men. We will test how dietary manipulation of folate (both depletion and supplementation compared to control diet) will affect prostate epithelium growth and phenotype. Further, we will investigate the molecular mechanisms underlying these processes at the genetic and epigenetic level. The results of our study will allow us to establish a mechanistic relationship between dietary folate manipulation and the genetic/epigenetic damage that drives tumorigenesis in prostatic epithelium. CaP arises as a slow-growing malignancy typically exhibiting a long lag period between initiation of disease and presentation of clinical symptoms. Dietary manipulation of folate might provide an effective tool to delay and control CaP progression from an indolent state to a highly aggressive state. Such a dietary tool could result in a major decrease in CaP mortality allowing patients to live with a non-aggressive disease. PUBLIC HEALTH RELEVANCE: Cancer of the prostate is the most commonly diagnosed cancer in American men. This proposal will study the effect of dietary folate deficiency and supplementation on the biology of prostate cancer in a mouse model. We predict that supplementation will reduce the rate at which the integrity of the genome is compromised by buttressing the over-burdened metabolic pathways requiring folate in prostate cells. If so, this could have very important implications for prostate cancer in men allowing us to slow the progression in men showing the very first signs of prostate cancer and therefore significantly reducing mortality from this disease.